Barriers and facilitators for interventions to improve ART adherence in Sub-Saharan African countries: A systematic review and meta-analysis

Background The HIV/AIDS pandemic remains a significant public health issue, with sub-Saharan Africa (SSA) at its epicentre. Although antiretroviral therapy (ART) has been introduced to decrease new infections and deaths, SSA reports the highest incidence of HIV/AIDS, constituting two-thirds of the global new infections. This review aimed to elucidate the predominant barriers and facilitators influencing ART adherence and to identify effective strategies to enhance ART adherence across SSA. Methods A comprehensive review was conducted on studies examining barriers to ART adherence and interventions to boost adherence among HIV-positive adults aged 15 and above in SSA, published from January 2010 onwards. The research utilized databases like Medline Ovid, CINAHL, Embase, and Scopus. Included were experimental and quasi-experimental studies, randomized and non-randomized controlled trials, comparative before and after studies, and observational studies such as cross-sectional, cohort, prospective and retrospective studies. Two independent reviewers screened the articles, extracted pertinent data, and evaluated the studies’ methodological integrity using Joanna Briggs Institute’s standardized appraisal tools. The compiled data underwent both meta-analysis and narrative synthesis. Results From an initial pool of 12,538 papers, 45 were selected (30 for narrative synthesis and 15 for meta-analysis). The identified barriers and facilitators to ART adherence were categorized into seven principal factors: patient-related, health system-related, medication-related, stigma, poor mental health, socioeconomic and socio-cultural-related factors. Noteworthy interventions enhancing ART adherence encompassed counselling, incentives, mobile phone short message service (SMS), peer delivered behavioural intervention, community ART delivery intervention, electronic adherence service monitoring device, lay health worker lead group intervention and food assistance. The meta-analysis revealed a statistically significant difference in ART adherence between the intervention and control groups (pooled OR = 1.56, 95%CI:1.35–1.80, p = <0.01), with evidence of low none statistically significant heterogeneity between studies (I2 = 0%, p = 0.49). Conclusion ART adherence in SSA is influenced by seven key factors. Multiple interventions, either standalone or combined, have shown effectiveness in enhancing ART adherence. To optimize ART’s impact and mitigate HIV’s prevalence in SSA, stakeholders must consider these barriers, facilitators, and interventions when formulating policies or treatment modalities. For sustained positive ART outcomes, future research should target specific underrepresented groups like HIV-infected children, adolescents, and pregnant women in SSA to further delve into the barriers, facilitators and interventions promoting ART adherence.

stigma, poor mental health, socioeconomic and socio-cultural-related factors.Noteworthy interventions enhancing ART adherence encompassed counselling, incentives, mobile phone short message service (SMS), peer delivered behavioural intervention, community ART delivery intervention, electronic adherence service monitoring device, lay health worker lead group intervention and food assistance.The meta-analysis revealed a statistically significant difference in ART adherence between the intervention and control groups (pooled OR = 1.56, 95%CI:1.35-1.80,p = <0.01),with evidence of low none statistically significant heterogeneity between studies (I 2 = 0%, p = 0.49).

Conclusion
ART adherence in SSA is influenced by seven key factors.Multiple interventions, either standalone or combined, have shown effectiveness in enhancing ART adherence.To optimize ART's impact and mitigate HIV's prevalence in SSA, stakeholders must consider these barriers, facilitators, and interventions when formulating policies or treatment modalities.For sustained positive ART outcomes, future research should target specific underrepresented groups like HIV-infected children, adolescents, and pregnant women in SSA to further delve into the barriers, facilitators and interventions promoting ART adherence.

Background
The HIV/AIDS pandemic remains a pervasive global public health challenge.From the epidemic's inception until the close of 2021, approximately 84.2 million individuals (range: 64.0-113.0 million) contracted HIV, resulting in an estimated 40.1 million deaths (range: 33.6-48.6 million) due to the virus [1].In 2021 alone, there were 38.4 million people living with HIV, 1.5 million new infections, and between 510,000 and 860,000 AIDS-related deaths [1,2].Sub-Saharan Africa (SSA), or the World Health Organization (WHO) African region, continues to bear the heaviest HIV/AIDS burden.Here, nearly 1 in every 25 adults (3.4%) is living with HIV, comprising over two-thirds of the global HIV population [1,3].
After an HIV diagnosis, timely and effective linkage to care is pivotal [4,5].Currently, there is no cure for HIV.Anti-retroviral therapy (ART) remains the sole treatment that can prolong life and improve the quality of life of people living with HIV/AIDS (PLWHA) [5,6].ART has revolutionized the management of HIV, transforming a once-fatal disease into a manageable chronic condition [7].This therapy inhibits the virus' replication, reduces the patient's viral load, increases CD4 counts, and thus decreasing the patient's risk of opportunistic infections and hospitalizations.This boosts patient's quality of life and reduces mortality [8][9][10].As the patient's CD4 counts rises, their immune system is rejuvenated, effectively combating infections and HIV-related cancers [6].For ART to be effective, it must be consistently taken as prescribed [5,[7][8][9].When properly adhered to, ART minimizes the individual's viral load, prevents drug resistance, reduces the risk of transmission, and lowers treatment failure rates [6,[10][11][12].Conversely, inconsistent adherence can lead to drug resistance and compromised treatment efficacy [6].
Despite ART's potential benefits-enabling immune recovery and improving survival in PLWH [11], healthcare systems across SSA grapple with multiple challenges in scaling up ART provision.Key issues include suboptimal ART adherence, poor retention of PLWHA in care, and overloaded primary health care facilities [13].Such challenges might be contributing to observed ART non-adherence, particularly in regions with high disease prevalence [14].
Research has indicated that patient factors, the nature of the disease, treatment modalities, and the patient-healthcare provider relationship can impact adherence [15,16].Notable barriers encompass stigma, negative perceptions, lack of family and community support, status disclosure issues, unemployment, transportation challenges, insufficient nutrition, inadequate follow-ups, confidentiality concerns, and dependency on alternative therapies [17,18].Also, physical, economic, and emotional stress, travel away from home, business with other things, depression, alcohol or drug use, and ART dosing frequency have all been identified as barriers to adherence [19,20].On the positive side, several facilitators to ART adherence have been documented, including social support [21,22], HIV status disclosure, health improvement due to ART, use of reminder aids and receiving education and counselling [21,23].Community knowledge and understanding of the HIV infection, increasing collaboration between Western and Traditional providers, peer and family level support, decreasing cost and distance to ART clinic [24] as well as clear instructions for taking ART, service providers' positive attitude towards patients, benefits of adhering to ART and dangers of defaulting [23] have also been documented as factors facilitating ART adherence.Despite this plethora of research, comprehensive insights into the predominant barriers and facilitators common across all SSA countries remain sparse.
Patients on ART frequently face multifaceted barriers to consistent adherence, implying that a single intervention strategy may not suffice.Healthcare providers are thus encouraged to adopt a multifaceted approach-identifying at-risk patients and then tailoring support to address specific adherence obstacles [25].Documented interventions include home-based care, peer support, and specific treatment regimens [26].Also, cognitive behavioural interventions, education, treatment supporters, directly observed therapy, and active adherence reminder devices (such as mobile phone text messages) can help patients stick to their ART regimen [27].However, comprehensive data on interventions universally effective across SSA is scanty.
Considering the acute HIV burden in SSA, coupled with often under-resourced healthcare systems, understanding common barriers to and effective interventions for ART adherence is vital.Such insights can aid countries and organizations in framing effective strategies to curtail the pandemic in the region.This review, therefore, sought to pinpoint the prevalent barriers and facilitators influencing ART adherence and to unearth universally effective interventions that could enhance ART adherence across SSA.

Study design
This was a systematic review and meta-analysis of published studies that examined the barriers and facilitators to ART adherence and interventions that improved patients' adherence to ART in SSA countries.The review is reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) criteria (S1 File) [28].The review's protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO number CRD42021262256) and published in the Plos One journal [5].

Inclusion criteria
To select appropriate studies for this review, we used the PICO (population, intervention, comparator, and outcome) criteria.This allowed us to find and select the right studies that can address our research questions.Our inclusion criteria therefore comprised:

Population
This review included studies conducted between 2010 and 2023 on adult HIV-positive patients aged 15 or above in SSA.

Intervention
All studies that assessed the barriers and or facilitators to ART adherence and or evaluated interventions aimed at improving ART adherence among adults PLWH in SSA were included in this review.

Comparator
The interventions were either in comparison with other strategies to identify the most effective and/or were in comparison to no strategies/interventions (regular basic management).

Outcomes
The review included studies that assessed the following outcomes:

Types of studies
This review encompassed both experimental and quasi-experimental studies from SSA that evaluated barriers to ART adherence and interventions aimed at enhancing such adherence.Included studies consisted of randomized and non-randomized controlled trials, comparative pre-and-post studies, and various observational studies such as cross-sectional, cohort, prospective and retrospective investigations.The scope of this review was limited to studies conducted between 2010 and 2023 and involved adult participants aged 15 years and older.

Language
Only studies written in English and or French were included in this systematic review.

Search strategy
A three-step strategy was used to find published studies on barriers to ART adherence and interventions improving adherence to ART among adult PLWH in SSA.An initial search through the Medline Ovid database was first conducted using an analysis of text words found in the title and abstract, and the index terms used in describing the article.Secondly, keywords and index terms were identified to search for studies in selected databases.Finally, additional studies not found in the databases were looked for using the reference list of selected studies from the first and second searches.For this review, the databases that were searched included Medline Ovid, CINAHL, Embase, and Scopus.We also used search engines and directories such as Google scholar and Centres for Disease Control and Prevention (CDC) to search for unpublished studies.

Study screening and selection
Studies that were identified in searched databases were saved in Zotero and exported to the Covidence software for screening.The inclusion and exclusion criteria of this study was also imported to the Covidence software, and the software was used for title, abstract and full-text screening.After importing references and inclusion/exclusion criteria into the software, two independent reviewers screened titles of included studies following the eligibility criteria.All conflicts between the two reviewers were resolved either through discussion or by a third reviewer.This same procedure was applied for abstract screening.After the abstract screening, full texts of potentially eligible studies were retrieved and independently assessed for eligibility by two reviewers.Any conflicts or disagreement between the two reviewers over the eligibility of a given study were resolve in a similar manner as for the title and abstract screening.

Assessment of methodological quality
Two independent reviewers were used to assess the methodological validity of the studies that were selected for retrieval using standard critical appraisal tools from the Joanna Briggs Institute for Meta-Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI) (S3 File).Any disagreement between the two reviewers were settled through discussions or by a third reviewer.

Data extraction
Data was extracted from selected studies using a standardized data extraction tool from the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review instrument (S4 File).The extracted data included specific details about the barriers to ART adherence, strategies or interventions improving ART adherence, study populations, study methods and outcomes significant to the review question and objective.In the event of any missing data from a study, the corresponding author of the study was contacted to provide the missing data.The data were independently extracted by two reviewers.

Data synthesis
We conducted both a meta-analysis and a narrative synthesis of the various interventions improving ART adherence.The meta-analysis was done to identify the interventions with a significant impact in improving patients' adherence to ART.
For the meta-analysis, we first assessed the statistical heterogeneity with I 2 , which indicates the percentage of the total variation across studies; where 0% -40% indicates low heterogeneity, 30% -60% indicates moderate heterogeneity, 50% -90% indicates substantial heterogeneity, and 75% -100% indicates considerable heterogeneity.If there was a substantial amount of heterogeneity (75%), then sources of heterogeneity were examined through subgroup and sensitivity analyses.We also used Chi-square test to test the heterogeneity and considered Pvalues < 0.05 as statistically significant.We selected a fixed-effects model for significant homogeneous studies; otherwise, we applied a random-effects model.All outcomes were summarized using odds ratios (OR) and 95% confidence intervals (CI).An OR<1 indicated a lower rate of outcome among the group of patients who were treated following a given intervention.Publication bias was assessed by visual inspections of funnel plots and Egger's test.
For the narrative synthesis, we have described the barriers and facilitators to ART adherence and the interventions promoting adherence to ART, following Popay's guidance on the conduct of a narrative synthesis [29].The narrative synthesis has been structured by describing the studies following the barriers and facilitators assessed and the type of strategies used to improve ART adherence.The identified barriers and facilitators to ART adherence and the interventions improving adherence have first been presented in a table followed by detailed description of each ART adherence barrier and or facilitator and intervention promoting treatment adherence.

Confidence in cumulative evidence
The quality of evidence used in this review was assessed by the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) [30].

Characteristics of included studies
Twelve thousand five hundred and thirty-eight (12538) potential papers were identified for this study.After screening the titles and abstracts, 435 papers were selected for retrieval.When the papers were reviewed, 47 of the 435 papers retrieved for full text screening were found to fully meet our inclusion criteria.The papers were critically appraised using the JBI-MAstARI critical appraisal tool by two independent reviewers and 2 papers were further excluded due to missing outcome measures for different arms of the study.Only 45 papers (30 for narrative synthesis and 15 for meta-analysis) were finally found to be of sufficient quality and were retained (Fig 1).
For the meta-analysis, majority of the studies included were RCTs in design (n = 14), while more than half (16) of the studies included in the narrative synthesis were qualitative in design.Each included study was either conducted only in one SSA country or in two or more SSA countries.Participants in the studies were both adult male and female PLWH aged 15 and above.Details about the studies are summarized in Table 1.

Quality appraisal
Tables 2 and 3 presents the quality appraisal of studies included in this review.For the included non-randomized control studies, 17 of them had an overall high rate of methodological quality (>90%), 13 had a moderate methodological quality ranging between 80 and 90% and only one had a methodological quality rate of less than 80%.The variation in methodological quality was because some studies did not adequately explain how confounding factors were delt with, did not sufficiently explain participant follow up and the criteria used to objectively assess outcomes in a reliable way (Table 2).
For the included randomized control trials, 6 had a high methodological quality rate (>90%), 6 had a rate between 80-90% and 2 had a methodological quality rate of less than 80%.The variations in methodological quality among trials was because some trials did not conceal the allocation of treatment from allocators, outcomes of participants who withdrew from the trials were not described nor included in the analysis and those assessing outcomes were not blind to treatment allocation (Table 3).

Common barriers and facilitators to ART adherence in SSA
Thirty studies [18, reported barriers to ART adherence and 11 of the studies [31-34, 37, 39, 43, 46, 53, 55, 56] also reported facilitators to ART adherence.Both the barriers and  adherence monitoring device [69,72], lay health worker lead group intervention [73] and food assistance [74].The counselling intervention (either used alone or in combination with another intervention such as SMS), peer delivered intervention, food assistance, community ART delivery as well as lay health worker lead group interventions have a significant effect in improving patients' adherence to ART.However, incentives (either financial or in kind), SMS and electronic adherence monitoring device interventions have varying statistically significant or non-significant effects in different settings (Table 5).

Effect of interventions on ART adherence-meta-analysis
Fourteen RCTs and 1 cohort study reported ART adherence as an outcome.All 15 included studies were pooled in the meta-analysis.The total number of participants in the pooled  studies were 3877 PLWH who were on ART.Of these 3877 participants, 2110 received an ART adherence intervention and 1520 of them were ART adherent after the intervention.Overall, the results of the pooled analysis from both the RCTs and cohort study included showed a statistically significant difference in ART adherence rates between the intervention and controlled groups (pooled OR = 1.56, 95%CI:1.35-1.80,p = <0.01),with evidence of low none statistically significant heterogeneity between studies (I 2 = 0%, p = 0.49) (Fig 2).
In the subgroup analysis of RCTs and cohort study, the individual and pooled ORs for ART adherence are shown in Fig 3 .The results of the pooled analysis from the RCTs showed a statistically significant difference in ART adherence between the intervention and control groups (pooled OR = 1.65, 95%CI:1.34-2.03,p = <0.01),with evidence of moderate none statistically significant heterogeneity between studies (I 2 = 41%, p = 0.06).Similarly, the result of the analysis from the cohort study showed a statistically significant difference in ART adherence between the intervention and control groups (OR = 2.87, 95%CI: 1.17-7.02;p = 0.02).
Furthermore, in the subgroup analysis of studies by region (West and Central African region, East African region, and Southern African region), the results of the pooled analysis from studies in the West and Central African as well as those from the East African region showed a statistically significant difference in ART adherence between intervention and control groups but with no statistically significant heterogeneity between studies.A moderate none statistically significant heterogeneity (I 2 = 44%, p = 0.13) was only observed in the Southern African region studies which also showed a none statistically significant difference in ART adherence between intervention and control groups ((pooled OR = 1.51, 95%CI:0.86-2.63,p = 0.15), (Fig 4).

Confidence in the evidence
The assessment of the quality of the evidence used in this review shows that there is high certainty of evidence in intervention effect on the domain of patients' adherence to ART.The certainty of evidence on the outcome domains of retention in care and CD4 cell counts is low.Lastly, certainty of evidence on the viral load outcome domain is very low (Table 6).This systematic review and meta-analysis synthesized existing evidence on ART adherence barriers, facilitators and strategies or interventions for improving patients' adherence to ART in SSA countries.We document that 30 studies included in this review reported barriers to ART adherence, 11 of them also reported facilitators to ART adherence and 15 studies reported interventions improving ART adherence in SSA.The common barriers reported are grouped under seven major factors: patient-related (age, use of alcohol or other drugs, forgetfulness, business with other things, non-status disclosure, limited HIV knowledge, leaving house without drugs, perceived wellness or feeling healthy), health system-related (poor clinic infrastructure, health workers knowledge and attitudes, long waiting times, poor service delivery, rupture of drugs), medication-related (side effects, pill burden/dosing, treatment fatigue), stigma (gossips, fear of status disclosure), poor mental health (depression, anger and hopelessness, sleep disorders, feeling overwhelmed with life demands), socioeconomic (unemployment, poverty, food insecurity, no disability grants, lack of partner/family support) and sociocultural-related (use of alternative medicines, intimate partner violence, religious beliefs/practices, belief in witch doctors, lack of community support) factors.Similarly, the common facilitators to ART adherence are also group under the same seven major factors as barriers and they include: patient-related (use of reminders, having routines, disclosing status and HIV/ ART education), health system-related (caregiver support, decentralization of ART care units, improved relationship with care providers), medication-related (awareness of regimen, benefits of ART), stigma (accept status, view ART as life-saving, improve knowledge and understanding of HIV/ART), poor mental health (motivation to be healthy for self and others, counselling, belief in eminent HIV cure discovery, desire to raise offspring), socioeconomic (disability grants, financial support) and socio-cultural-related (partner/family support, social support, community support, encouragement from community health workers).The interventions improving ART adherence include counselling, incentives, mobile phone short message service (SMS), peer delivered behavioural intervention, community ART delivery intervention, electronic adherence service monitoring device, lay health worker lead group intervention and food assistance.These interventions are either effective individually or when combined and the results of our meta-analysis revealed an improvement in ART adherence in favour of ART interventions.
There have been several reviews in the realm of ART adherence, each with its distinct scope and limitations.Some are somewhat dated, others might have methodological constraints, and a significant portion focuses exclusively on English-language publications.Specifically: a 2008 review centred on barriers to accessing antiretroviral treatment in developing nations, emphasizing studies from 1996 to 2007 and exclusively sourcing from PubMed, FamMed and Cochrane databases [79].A 2012 examination reviewed ART adherence trends in Cameroon, covering studies between January 1999 and May 2012 [80].Another review from 2003 to February 2019 addressed the efficacy of treatment supporter interventions for ART adherence in SSA, but it considered only English-language studies [81].A further review regarding strategies to bolster adherence in sub-Saharan Africa exclusively considered articles from PubMed, Medline and Google Scholar databases [82].
Our study fills a unique niche in this spectrum: it provides an all-encompassing view of barriers, facilitators, and interventions to enhance ART adherence in SSA, embracing both English and French publications.This makes our review distinct as no similar comprehensive study has been identified.
Delving into our findings, we observed that the reported barriers align with those from other reviews, specifically those relating to patient factors, medication, stigma and health services [25].Nonetheless, our review offers a broader scope, encompassing barriers that have been somewhat overlooked by others, like transport [83] and food insecurity issues [84].Other reviews focused exclusively on population and health system level barriers [79] and depression and alcohol use related barriers [85].Furthermore, our findings regarding facilitators mirror those from other reviews, noting common themes like social support, reminders, status disclosure and the importance of establishing robust patient-provider relationships [86].
Regarding interventions, our review highlights a variety of strategies, some potent as standalone measures, and others more effective in tandem with complementary interventions.This is consistent with another review asserting the necessity of multiple interventions due to the diverse barriers faced by ART patients [25].While our review doesn't single out the most impactful intervention, our meta-analysis underscores an overarching improvement in adherence when ART interventions are implemented.This is in line with other analyses which have demonstrated increased adherence with the introduction of interventions [87].It is also noteworthy that some specific groups, like pregnant and lactating women, show heightened adherence when given targeted interventions [88].Community-based ART delivery, as observed in other reviews, also emerges as a potent strategy, enhancing patient retention, accessibility to HIV services, and overall treatment engagement [89][90][91].

Strengths and limitations
This review has the following strengths-eligible studies were identified through a comprehensive search on several databases and sources, it included recent articles published in SSA However, our review is limited by the fact that we included some cohort studies which may bias the overall estimate effect due to unmeasured confounding not adjusted for in multivariable analysis.Also, included studies for our meta-analysis did not measure the outcome (adherence) in the same way nor using the same tool; this might impact the results of our pooled analysis.Lastly, we did not include unpublished studies and might have missed some eligible articles.

Conclusion
The barriers and facilitators to ART adherence in SSA countries can be categorized under seven primary factors: patient-related, health system-related, medication-related, stigma, poor mental health, socioeconomic and socio-cultural-related factors.Common interventions that enhance ART adherence encompass counselling, incentives, mobile phone short message services (SMS), peer delivered behavioural intervention, community ART delivery intervention, electronic adherence service monitoring device, lay health worker lead group intervention and food assistance.These strategies prove effective either as standalone approaches or in conjunction with other methods.To harness the full potential of ART and mitigate the HIV burden in SSA countries, stakeholders engaged in HIV prevention and treatment must recognize and integrate these barriers, facilitators, and adherence enhancing interventions when formulating policies or crafting treatment strategies.Ensuring sustained optimal outcomes from ART may necessitate further research, particularly focusing on specific underrepresented demographics such as HIV-infected children, adolescents, and pregnant women in SSA.This research will aim to uncover the most appropriate barriers, facilitators and interventions tailored to each group's unique needs.
Primary outcome: Proportion of patients adhering to treatment following implementation of specific strategies.Secondary outcomes: Proportion of patients retained in care, prevalence of opportunistic infections and or the worsening/severity of the patient's stage of HIV infection following specific treatment interventions.Included studies measured viral load and CD4 cell counts as an indication of the treatment adherence and efficacy.

Table 2 . JBI critical appraisal results for non-randomize control trial studies.
not applicable * Score is out of 8 due to an inapplicable item https://doi.org/10.1371/journal.pone.0295046.t002